Cancer research has shown an increasing interest in the use of monoclonal antibodies as a therapeutic. Raised in a similar fashion to diagnostic antibodies, therapeutic antibodies are aimed at specifically targeting tumor cells. The use of therapeutic monoclonal antibodies has been hampered in the past primarily because of issues related to the antigenicity of the protein. Monoclonal antibodies are a mouse product, and therefore generate an anti-murine response when injected into humans. This so-called HAMA (human anti-mouse antibody) response has imposed a great limitation on the use of monoclonal antibodies, as repeated dosing is nearly always precluded. In addition, serious complications, such as serum sickness, have been reported with the use of these agents. With the advent of chimeric and humanized antibodies, the therapeutic benefit of monoclonals is being realized. Using recombinant DNA technology, it is possible for a monoclonal antibody to be constructed by joining the variable or antigen recognition site of the antibody to a human backbone. This construction greatly decreases the incidence of blocking or clearing of the foreign antibodies from the host. This development allows for multiple doses of antibody to be given, providing the opportunity for reproducible and sustained responses with this therapy.
Recent cancer research has focused on the use of recombinant humanized monoclonal antibodies for the treatment of cancers whose cells overexpress the protein p185HER2. This 185-kDa growth factor receptor is encoded by the her-2 proto-oncogene, also referred to as neu and c-erbB-2 (Slamon et al. (1987) Science 235:177-182). The her-2 gene is closely related to, but distinct from, the gene encoding epidermal growth factor receptor (EGFR). Amplification of this gene has been linked to neoplastic transformation in human breast cancer cells (Slamon et al. (1987) supra). Overexpression of this protein has been identified within 20-30% of breast cancer patients, where it correlates with regionally advanced disease, increased probability of tumor recurrence, and reduced patient survival. As many as 30-40% of patients having gastric, endometrial, salivary gland, non-small cell lung, pancreatic, ovarian, peritoneal, prostate, or colorectal cancers may also exhibit overexpression of this protein.
The most widely recognized monoclonal antibody targeting HER2 receptor function is marketed under the tradename Herceptin® (Genentech, Inc., San Francisco, Calif.). This recombinant humanized monoclonal antibody has high affinity for p185HER2. Early clinical trials with patients having extensive metastatic breast carcinomas demonstrate the ability of this monoclonal antibody to inhibit growth of breast cancer cells that overexpress HER2 (Baselga et al. (1996) J. Clin. Oncol. 14(3):737-744). In one such trial, monotherapy with Herceptin® in metastatic breast cancer patients yielded an overall response rate of 14% (2% complete responders and 12% partial responders). The median duration of response was 9.1 months, median survival was 12.8 months (ranging from 0.5 to 24+ months). Twenty-four percent of the patients were progression free at 5.8 months (Genentech, Inc., data on file). Degree of overexpression of p185HER2 was predictive of treatment effect. In another clinical trial, monotherapy with Herceptin® yielded objective responses in 5 out of 43 assessable metastatic breast cancer patients (11.6%).
Interleukin-2 (IL-2) is a potent stimulator of natural killer (NK) and T-cell proliferation and function (Morgan et al. (1976) Science 193:1007-1011). This naturally occurring lymphokine has been shown to have anti-tumor activity against a variety of malignancies either alone or when combined with leukotriene-activated killer (LAK) cells or tumor-infiltrating lymphocytes (see, for example, Rosenberg et al. (1987) N. Engl. J. Med. 316:889-897; Rosenberg (1988) Ann. Surg. 208:121-135; Topalian et al. (1988) J. Clin. Oncol. 6:839-853; Rosenberg et al. (1988) N. Engl. J. Med. 319:1676-1680; and Weber et al. (1992) J. Clin. Oncol. 10:33-40). Although the anti-tumor activity of IL-2 has best been described in patients with metastatic melanoma and renal cell carcinoma, other diseases, notably lymphoma, also appear to respond to treatment with IL-2. However, high doses of IL-2 used to achieve positive therapeutic results with respect to tumor growth frequently cause severe toxicity effects, including capillary leak, hypotension, and neurological changes (see, for example, Duggan et al. (1992) J. Immunotherapy 12:115-122; Gisselbrecht et al. (1994) Blood 83:2081-2085; and Sznol and Parkinson (1994) Blood 83:2020-2022). Studies have shown that IL-2 augments antibody-dependent cellular cytotoxicity in vitro, and potential natural killer cell effectors may be expanded and activated in vivo with low dose IL-2 (Cancer Immunol. Immunother. 46(1998):318).
Although both of these agents exhibit promising anti-tumor activity, their therapeutic potential for cancer patients needs further examination. Cancers whose cells overexpress the HER2 receptor can be particularly recalcitrant to treatment. New methods of therapy that provide a more aggressive approach are needed.